INTRASTRIATAL IMPLANTATION OF INTERLEUKIN-1 - REDUCTION OF PARKINSONISM IN RATS BY ENHANCING NEURONAL SPROUTING FROM RESIDUAL DOPAMINERGIC-NEURONS IN THE VENTRAL TEGMENTAL AREA OF THE MIDBRAIN

Intrastriatal implantation with dopaminergic or nondopaminergic tissue can elicit behavioral recovery in parkinsonian animals. Because in th ese animals, especially in ethyl-4-phenyl-1,2,3,6-tetrahydropyridine-l esioned monkeys, there are still considerable numbers of dopaminergic neurons left in the mesencephalon, implantation-induced trophic effect s on host residual dopaminergic neurons have been suggested as a mecha nism underlying the behavioral recovery. Gliosis around the graft is a universal finding in any implantation procedure and is probably media ted by interleukin-1 (IL-1); in addition, activated astrocytes secrete several neurotrophic factors in vitro. Therefore, the authors postula ted that trophic effects from IL-1-induced gliosis may be a ''final co mmon pathway'' for recovery in parkinsonian animals after implantation . Hemiparkinsonism was induced in rats by injection of 6-hydroxydopami ne either directly into the substantia nigra or into the median forebr ain bundle. The substantia nigra-lesioned rats showed complete depleti on of dopaminergic neurons in the substantia nigra but sparing of thos e in the ventral tegmental area, whereas the median forebrain bundle-l esioned animals had depletion of dopaminergic cells in the substantia nigra and the ventral tegmental area. Polymer pellets containing eithe r slow-released IL-1 alpha and beta or placebo pellets were implanted in the caudate nucleus on the lesioned side in both groups. The rats' rotational response to amphetamine was tested weekly for 8 weeks. Sele ctive substantia nigra-lesioned rats with implantation of IL-1 pellets had a 45% reduction in amphetamine-induced rotation, whereas placebo- implanted substantia nigra-lesioned rats had a 14% reduction in rotati on. In the median forebrain bundle-lesioned group, neither IL-1 nor pl acebo implantation elicited any effect on turning. Immunohistochemical staining for glial fibrillary acidic protein was markedly increased s urrounding the IL-1 pellets compared to the placebo pellets. In the se lective substantia nigra-lesioned rats with IL-1 pellets implanted in the caudate nucleus, a considerable number of tyrosine hydroxylase imm unoreactive (TH-IR) fibers were observed in the medial and middle port ions of the caudate nucleus. Fewer TH-IR fibers were seen in the rats with placebo-bearing pellets. These results suggest that neurotrophic activities mediated by IL-1 and reactive astrocytes might be a common path through which tissue trauma and some tissue transplants exert the ir beneficial effects in parkinsonian animals. Furthermore, most of th e sprouted dopaminergic fibers induced by IL-1 in the caudate nucleus come from dopaminergic neurons in the ventral tegmental area.